Prior Ophthalmologic Uses of Urea
U.S. Pat. Nos. 5,629,344 (Chariton) and 5,470,881 (Chariton) describe certain therapeutic applications of urea preparations to the eye. These prior patents specifically describe non-aqueous ointments and other non-aqueous preparations of urea for use in the eye, pointing out that aqueous solutions of urea were believed to be impractical for use in the eye. For example, these prior patents state as follows: “One of the reasons urea has not been used in treating eye disorders is that it will hydrolyze in aqueous vehicles thus producing ammonia as a byproduct. Ammonia is toxic to the eye, and thus urea in an aqueous solution would be impractical for use as an ophthalmic medicament.” Thus, prior to Applicant's invention, aqueous solutions of urea or urea derivatives were thought to be unstable and potentially toxic to the eye.
Anatomic and Physical Properties of the Cornea
The cornea is the first and most powerful refracting surface of the optical system of the eye. Production of a sharp image at the retinal receptors requires that the cornea be transparent and of the appropriate refractive power. The average corneal thickness of a normal cornea is 0.56 mm in persons under 25 years of age; this thickness slowly increases with age to become 0.57 in persons over 65 years of age. The cornea is somewhat thicker in the periphery than the center. The thickness of the cornea is greatest after the eyes have been closed for some time, as after sleeping, this thickness decreases slightly when the eyes are opened and exposed to the dehydrating effects of the air.
The cornea is composed of six layers: a) Epithelium. b) Basement membrane. c) Bowman's membrane. d) Stroma. e) Descemet's membrane. f) Endothelium.
a) Epithelium: The epithelium consists of 5-6 layers of cells. The most superficial cells are flat overlapping squamous cells. The middle layer consists of cells that become more columnar as the deeper layers are approached. The innermost layer (basal) is made up of columnar cells packed closely together. All the cells are held together by a cement substance. Also, the cell surfaces form processes that are fitted into corresponding indentations of adjacent cells and connected in places by attachment bodies called desmosomes. The basal cells are connected to the basement membrane by hemidesmosomes. The epithelium represents 10% of the total wet weight of the cornea. Water in the epithelium represents 70% of the wet weight.
Although the epithelium consists of 5-6 layers of cells, the healthy epithelium is very strongly attached to each other by desmosomes as well as to the Basement membrane by hemidesmosomes.
b) Basement membrane: Between the columnar epithelial cells and Bowman's membrane is a basement membrane from 60-65 nm thick. The basement membrane has been examined histochemically and found to be similar to other basement membranes.
c) Bowman's membrane: Bowman's layer is a sheet of transparent tissue about 12 μm thick, without structure as seen by light microscopy. Under electron microscopy it appears to be made up of uniform fibrils, probably of collagenous material, running parallel to the surface. Bowman's layer possesses little resistance to any pathologic process, and is easily destroyed and never regenerates.
d) Stroma: The Stroma comprises about 90% of the whole cornea. The Stroma is composed of layers of lamellae, each of which runs the full length of the cornea; although the bundles interlace with one another, they are nearly parallel to the surface. The cell bodies, called keratocytes, are flattened, so they too lie parallel to the surface, and their cell processes interlace with one another. This arrangement of the fibers gives optical uniformity to the cornea. The Stroma comprises about 90% of the whole cornea. The Stroma is composed of differentiated connective tissue containing 75% to 80% water on a wet weight basis. The remaining solids 20% to 25% is collagen, other proteins, and glycosaminoglycans or mucopolysaccharides constitute the major part. The collagen fibrils are neatly organized and present the typical 64 to 66 nm periodicity of collagen fibrils separated from each other by the ground substance. The size, regularity, and precise spacing of the fibrillar structures are the physical characteristics essential for corneal transparency.
The glucosaminoglycans (GAG, mucopolysaccharides) represent 4% to 4.5% of the dry weight of the cornea. GAG are localized in the interfibrillar or interstitial space, probably attached to the collagen fibrils or to soluble proteins of the cornea. The GAG plays a role in corneal hydration through interaction with electrolytes and water. Three major GAG fractions are found in the corneal Stroma: keratin sulfate (50%), chondroitin (25%), and chondroitin sulfate A (25%). GAG's have been implicated in the maintenance of the corneal hydration level and transparency.
e) Descemet's Membrane: Is made of type IV collagen, unlike the corneal Stroma, there are no significant amounts of sulfated GAG in the Descemet's membrane. The collagen in this membrane is insoluble except in strong alkali or acid and is more resistant to collagenase than corneal stroma collagen. Jakus2 has observed with the electron microscope that this membrane has collagen like structure of great regularity. Descemet's membrane is highly elastic and represents a barrier to perforation in deep corneal ulcers.
f) Endothelium: The endothelium is a single layer of cells lining Descemet's membrane. Its inner surface is bathed by the aqueous humor. In humans the endothelium cell layer has limited, if any, reproductive capacity. Aging causes cell loss, and the remaining cells enlarge and spread so that Descemet's membrane remains completely covered.6 therefore endothelial cell density, expressed as cells per unit area, decreases with age. Similarly, cell loss from trauma, inflammation, or surgery is compensated for by increased cell size and decreased cell density.
Corneal metabolism embraces a series of chemical processes by which energy is obtained and utilized for the normal functions of the cornea. In the cornea, energy is needed for maintenance of its transparency and dehydration. Energy in the form of ATP is generated by the breakdown of glucose into lactic acid and into carbon dioxide and water (i.e., Krebs Cycle). The cornea obtains glucose mainly from the aqueous humor. The tears and limbal capillaries appear to contribute minimal amounts of glucose and Oxygen for corneal metabolism.
Most of the oxygen consumed by the cornea is taken in by the epithelium and the endothelium. The oxygen consumption of the epithelium and endothelium can be approximately 26 times that of the stroma. The corneal endothelium gets most of its required oxygen from the aqueous humor, while the corneal epithelium gets much of its oxygen from either the capillaries at the limbus or from the oxygen dissolved in the pre-corneal film.
Methods for the Refractive Correction of the Eye:
Radial keratotomy (RK) is a surgical procedure to improve myopia by changing the corneal curvature. This is achieved by making several deep incisions in the cornea in a radial pattern. The eye surgeon makes 4, 8, or 16 incisions so as to flatten the curvature of the central cornea, thus correcting the patient's vision. The main drawbacks of RK include, a) It can only be used to correct low levels of myopia. b) This surgical procedure cannot correct hyperopia. c) RK procedure seriously weakens the cornea and creates corneal scars. d) The corneal curvature changes are temporary and frequently continue to change with time.
Photorefractive keratectomy (PRK) is a surgical procedure that uses the excimer laser, which is controlled by a computer. With the PRK procedure, the excimer laser ablates and sculpts the corneal surface to the desired shape to correct the patient's vision. There are a combination of lasers with a combination of computer controls that can reliably treat myopia, hyperopia, and astigmatism. Since PRK is a surgical procedure, it can result in complications. Infection is the most serious complication resulting from the ablation of a large area of the corneal epithelium. In addition delayed corneal healing because of the absence of the corneal epithelium, corneal haze, corneal scarring, over correction or under-correction and development of astigmatism are other complications of PRK. These complications must be treated with medications or further surgery.
Laser in-situ keratomileusis11 (LASIK) is a surgical procedure that is a variation on PRK involving an excimer laser and a precise cutting tool called a microkeratome. The microkeratome is used to make a 150-175 micron circular flap of the cornea. The circular flap is flipped back, as if on a hinge, to expose the stromal layer of the cornea. With the flap folded back, the refractive eye surgeon now ablates the stroma and makes the refractive correction using the excimer laser. The circular corneal flap is repositioned on the ablated cornea to complete the procedure. With a precision laser treatment and normal reattachment and healing of the corneal flap, the refractive results of good vision correction are very rapid. There is, however, a significant list of potential complications and risks associated with LASIK procedure; failure of the microkeratome to leave a hinge on the corneal flap with the first incision, loss of the corneal flap after the operation, slipping of the flap and healing off center, first incision is too deep or too shallow, corneal epithelium ingrowths into the stroma, infection of the cornea, corneal ectasia, loss of visual acuity from scarring and optical distortion of the collagen structure of the stroma.
Laser epithelial keratomileusis (LASEK) is a surgical procedure that is a variation on PRK involving an excimer laser that combines the advantages and eliminates the disadvantages of PRK and LASIK. A 7.0 mm circular area of the epithelium is marked with a Hoffer trephine centered over the pupil. The corneal epithelium is removed by using a blunt spatula, or is exposed to 20% isopropyl alcohol solution which allows the corneal epithelium to be peeled off. Using the excimer laser the surgeon ablates and sculpts the corneal surface to the desired shape to correct the patient's vision. At the end of the procedure the corneal epithelial flap created by the alcoholic solution is placed back onto the ablated cornea, a drop of antibiotic, a drop of non-steroidal anti-inflammatory agent and a therapeutic contact lens is applied to the corrected eye. The epithelial defect created by the scrapping of the corneal epithelium, or by peeling of the epithelium after the application of alcoholic solution is completely closed within a few days. With a precision laser treatment and normal healing of the corneal epithelium, the refractive results of good vision correction are very rapid. There are, however, a few potential complications and risks associated with LASEK procedure; infection of the cornea because of the epithelial defect as a result of epithelial scrapping, use of alcoholic solution causes extensive damage to the peeled corneal epithelium minimizing the benefits of the reapplied corneal epithelium.
Thermokeratoplasty is another corneal reshaping method. In this procedure heat at 55° C. to 58° C. is applied to the collagen fibers of the cornea to induce shrinkage without the destruction of the tissue. The shrinkage of the collagen fibers result in the change of the mechanical properties and flattening of the cornea, thus achieving refractive correction. U.S. Pat. No. 4,881,543 describes the use of microwave electromagnetic energy to shrink the collagen of the cornea. U.S. Pat. No. 5,779,696 describes the use of light energy to reshape the cornea. All of these systems of Thermokeratoplasty have a shortcoming that is the treated corneas are unstable after the treatment.
Orthokeratology is a non-surgical procedure designed to correct refractive errors by reshaping the cornea to the corneal curvature required to achieve emmetropia. This is accomplished by applying a series of hard contact lenses that change the corneal curvature until the desired curvature is achieved. However once the desired curvature has been produced, retainer hard contact lenses must be worn to stabilize the results otherwise regression will occur.
Enzyme Orthokeratology is related to traditional Orthokeratology in that it is defined primarily as a contact lens procedure of correcting refractive errors of the eye by reshaping the cornea to the curvature required for emmetropia. The system is enhanced by enzymatically softening the cornea, and reshaping is obtained in a shorter period of time, and retainer lenses may not be required for good visual acuity after removal of the contact lens from the eye and regression will not be a problem.
Chemical Orthokeratology is related to traditional Orthokeratology in that it is defined primarily as a contact lens procedure of correcting refractive errors of the eye by reshaping the cornea to the curvature required for emmetropia. The system is enhanced by applying topically or by intra-stromal injection a chemical that is not an enzyme and softening the cornea, and reshaping is obtained in a shorter period of time, and retainer lenses may not be required for good visual acuity after removal of the contact lens from the eye and regression will not be a problem.